Enantioselective Synthesis of α-Quaternary Amino Acids by Alkylation of Deprotonated α-Aminonitriles

Article abstract of DOI:10.1021/acs.joc.5b00868

A series of α-quaternary arylglycines were prepared in high optical purity (up to 98% ee) by α-alkylation of deprotonated α-aminonitriles derived by the Strecker reaction from (4S,5S)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane. The procedure includes only chromatographic purification of the final products and is devoid of chromatography or crystallization operations on intermediates to raise the optical purity.

Full text of DOI:10.1021/acs.joc.5b00868

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Note
Enantioselective Synthesis of alpha-Quaternary Amino
Acids by Alkylation of Deprotonated alpha-Aminonitriles
Isabelle Netz, Murat Kucukdisli, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00868 • Publication Date (Web): 29 May 2015
Downloaded from http://pubs.acs.org on June 1, 2015
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Enantioselective Synthesis of α-Quaternary Amino Acids by
Alkylation of Deprotonated α-Aminonitriles
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Isabelle Netz, Murat Kucukdisli, and Till Opatz*
Institute of Organic Chemistry, Johannes GutenbergꢀUniversity, Duesbergweg 10ꢀ14, 55128
Mainz, Germany. eꢀmail: opatz@uniꢀmainz.de
TOC Graphics
H3C CH3
H3C CH3
1) diastereoꢀ
selective
alkylation
O
O
O
O
O
HCN
H2N CO2H
R1
R2
+
R1
H
2) removal of
auxiliary
NH2
HN
R1
CN
R1 = aryl,
R2 = alkyl
80 98% ee
Abstract
A series of αꢀquaternary arylglycines was prepared in high optical purity (ee up to 98%) by αꢀ
alkylation of deprotonated αꢀaminonitriles derived by Strecker reaction from (4S,5S)ꢀ5ꢀ
aminoꢀ2,2ꢀdimethylꢀ4ꢀphenylꢀ1,3ꢀdioxane. The procedure only includes the chromatographic
purification of the final products and is devoid of chromatography or crystallization operations
on intermediates to raise the optical purity.
αꢀAmino acids play a key role in the machinery of life. Consequently, their asymmetric
synthesis has become an important task for synthetic organic chemistry.1ꢀ5 While αꢀ
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quaternary αꢀamino acids are nonꢀproteinogenic, they do occur in nature and proved to be
useful as pharmaceuticals (e.g. methyldopa) or as building blocks for the construction of
peptidomimetics.6,7 Consequently, a variety of synthetic methods has been developed for
their synthesis, both in racemic or nonꢀracemic form.8ꢀ18 The pioneering chemical synthesis of
αꢀamino acids reported by Adolph Strecker in 1850 made use of their close relationship with
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αꢀaminonitriles and even today, the Strecker synthesis is still used for the industrial scale
synthesis of αꢀamino acids like methionine.19 Due to the strong anion stabilizing capacity of
the nitrile group and the latent iminium ion reactivity,20ꢀ23 αꢀaminonitriles are not only useful
precursors to amino acids but also versatile building blocks for the synthesis of a wide variety
of nitrogenꢀcontaining compounds24,25 including diverse Nꢀheteroarenes,26ꢀ28 aliphatic amine
derivatives29,30 or alkaloids31ꢀ39. We found that Nꢀmonoꢀ and Nꢀunsubstituted αꢀaminonitriles
derived from aromatic or heteroaromatic aldehydes can be deprotonated quantitatively in αꢀ
position to furnish stabilized αꢀaminocarbanion equivalents and in contrast to their
counterparts derived from aliphatic aldehydes, no Nꢀprotection is required.40 Since the
resulting anions should be suitable for the synthesis of αꢀquaternary αꢀamino acids through
Cꢀalkylation and subsequent hydrolysis, several removable nitrogenꢀbound auxiliaries were
tested for controlling the stereochemistry of the alkylation step. The use of various
substituted 1ꢀphenylethylamineꢀtype auxiliaries met with limited success and
diastereoselectivities of 10:1 were not surpassed. In contrast, (4S,5S)ꢀ5ꢀaminoꢀ2,2ꢀdimethylꢀ
4ꢀphenylꢀ1,3ꢀdioxane (1) proved to be highly effective and provided excellent
diastereoselectivities of up to 99:1. In contrast to the also highly efficient 2ꢀsulfinylarene type
auxiliary employed by Ruano and coworkers,41 it can be removed by oxidation after
hydrolysis of the nitrile function permits a straightforward access to αꢀquaternary
arylglycines.42,43
Auxiliary 1 had been successfully employed by Weinges et al.42ꢀ44 for the synthesis of αꢀ
amino acids by means of a diastereoselective crystallization of its Strecker products with
aldehydes or ketones followed by hydrolysis and oxidative degradation of the chiral template.
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Being readily available from acetone, nitromethane, formaldehyde, and benzaldehyde as a
byꢀproduct of an industrialꢀscale synthesis of the antibiotic chloramphenicol, the recycling of
1 is expendable. In the 1990’s, the Enders group employed Strecker products derived from
the Nꢀmethyl analogue of 1 as chiral acyl anion equivalents for diastereoselective 1,4ꢀ
additions to α,βꢀunsaturated carbonyl compounds.45ꢀ47
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The reaction of the hydrochloride salt of 1 with benzaldehyde (2a) and 2ꢀnapththaldehyde
(2b) in the presence of KCN furnished the aminonitriles 3a and 3b as single diastereomers
after crystallization from the reaction medium in 82% and 67% yield, respectively. Their
deprotonation with potassium bis(trimethylsilyl)amide (KHMDS) in THF at –78 °C furnished
the corresponding potassium keteneiminates which were αꢀalkylated with various alkyl and
benzyl halides to the αꢀquaternary aminonitriles 4 (Scheme 1).
Scheme 1. Synthesis of αꢀaminonitriles 4 by αꢀalkylation
The diastereoselectivity of the alkylation was determined by 1H NMR spectroscopy as well as
by HPLCꢀMS of the crude reaction mixture after an extractive workup (vide infra).
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Since the alkylation products were prone to spontaneous dehydrocyanation during attempted
chromatographic purification and were inert to acetylation, tosylation, and
alkoxycarbonylation to increase their stability, they were directly subjected to the acidic
hydrolysis of the nitrile group as well as the oxidative removal of the auxiliary. As already
reported by Weinges et al.,42ꢀ44 lactones 5 were formed upon treatment of compounds 4 with
hydrochloric acid. Double oxidative C–Cꢀbond cleavage catalyzed by RaneyꢀNickel with
aerial oxygen as the stoichiometric oxidant produced the αꢀamino acids 6 which were purified
by preparative HPLC (Scheme 2). While compounds 5 were obtained in low purity as judged
by NMR, the purity increased upon removal of the auxiliary.
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Scheme 2. Hydrolysis and oxidative removal of the auxiliary to produce amino acids 6.
The optical purity of the products was determined by derivatization with Marfey’s reagent (1ꢀ
fluoroꢀ2,4ꢀdinitrophenylꢀ5ꢀL
ꢀalanine amide) and analytical HPLC.48,49 The racemic products
used as HPLC standards were synthesized via BuchererꢀBergs reaction of the corresponding
ketones for comparison.50,51 The results are summarized in Table 1.
Table 1. Auxiliaryꢀcontrolled synthesis of αꢀquaternary arylglycines 6
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Yield from
Strecker-product
3
entry
product
R1
R2–X
e.r.a
eea
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
Ph
Ph
MeI
EtBr
33%
74%
68%
33%
21%
81%
49%
96:4
98.5:1.5
95.5:4.5
98:2
92%
97%
91%
96%
80%b
>98%
94%
Ph
BnBr
Ph
nꢀPrBr
iꢀPrBr
MOMCl
EtBr
Ph
90:10b
>99:1
97:3
Ph
6g
2ꢀNaph
a Determined by HPLC of the αꢀamino acids after derivatization with Marfey’s reagent.
b Approximate value due to the presence of impurities.
With the sole exception of the isopropyl substituted compound 6e (Table 1, entry 5), all
products were obtained with enantioselectivities of 91 to >98% ee, demonstrating the high
degree of stereocontrol exerted by the Weinges auxiliary.
Comparison of the optical rotation of compounds 6a–e with literature values confirmed the Rꢀ
configuration in each case (all compounds except for 6c are levorotatory). Presumably, the
shielding of the Reꢀface of the keteneiminate βꢀcarbon by the phenyl group of the auxiliary is
responsible for the observed asymmetric induction (Figure 1).
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Figure 1. Model for the stereoselective alkylation
Direction of attack and position of the other arene moiety are identical to the model for
Weinges’ diastereoselective HCN addition to arylaldimines derived from 1.44,24 A highly
similar spatial arrangement is also reflected in the Xꢀray structure of the THFꢀcomplex of the
lithiated Nꢀmethyl derivative of 1 published by Enders et al.52 who consistently observed Siꢀ
side attack in their 1,4ꢀadditions.
In summary, a highly effective diastereoselective auxiliaryꢀcontrolled synthesis of αꢀ
quaternary arylglycines based on the αꢀalkylation of deprotonated αꢀaminonitriles derived
from (4S,5S)ꢀ5ꢀaminoꢀ2,2ꢀdimethylꢀ4ꢀphenylꢀ1,3ꢀdioxane was developed. The products were
obtained in high optical purity without the need for the purification of intermediates by
chromatography or crystallization. To the best of our knowledge, this represents the first
stereoselective alkylation of deprotonated Nꢀmonosubstituted αꢀaminonitriles for the
preparation of αꢀamino acids. While the synthesis of purely aliphatic αꢀamino acids requires
the introduction of a removable Nꢀprotecting group (e.g. benzyl or PMP), high inductions
have already been demonstrated for the Nꢀmethyl derivative of the Weinges auxiliary.
Experimental Section
Materials and Methods
All reactions requiring the exclusion of air and/or moisture were conducted in flameꢀdried
glassware under an argon atmosphere. THF was distilled from potassium/benzophenone
under argon atmosphere. DCM was dried over calcium hydride and distilled under argon
atmosphere. Ethyl acetate and cyclohexane were purchased in technical quality and were
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purified by distillation. All other chemicals and solvents were purchased from commercial
suppliers and used without prior purification unless otherwise stated. Flash chromatography
was performed on silica of 25–40 ꢁm particle size. Alternatively, an automatic gradient flash
chromatographic system with integrated UV detector was used. NMR spectra were recorded
on 300 MHz, 400 MHz, and 600 MHz spectrometers using standard pulse sequences.
Chemical shifts are expressed in ppm relative to tetramethyl silane referenced to the residual
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1
1
solvent signals (CDCl3: H: δ = 7.26 ppm, 13C: δ = 77.16 ppm; D2O: H: δ = 4.79 ppm;
1
CD3OD: H: δ = 3.31 ppm; 13C: δ = 49.00 ppm). HPLCꢀMSꢀ and ESIꢀMSꢀanalyses were
performed on high pressure gradient systems with diode array detectors. ESIꢀHRMS was
performed on a QꢀTOF instrument with a dual source and a suitable external calibrant.
Analytical HPLC: ACE3ꢀC18PFP (3 ꢁm particle size, 150 x 4.6 mm), flow 1.0 mL/min, 40 °C.
Preparative HPLC: ACE5ꢀC18PFPꢀcolumn (5 ꢁm particle size, 150 x 30 mm), flow 37.5
mL/min, 21 °C. TLC was performed on aluminaꢀbacked silica plates (0.25 mm, 60 F254). IR
spectra were recorded on an FTIR with a diamond ATR unit. Optical rotations were
measured at 546 nm and 576 nm and were extrapolated to 589 nm using the Drude
equation. Melting points were measured on an electrothermal apparatus with a digital
thermometer.
General procedure for the synthesis of aminonitriles 3.
The title compounds were prepared according to a modification of a protocol by Enders et
al.45 (4S,5S)ꢀ(+)ꢀ5ꢀAminoꢀ2,2ꢀdimethylꢀ4ꢀphenylꢀ1,3ꢀdioxane (1) was dissolved in
methanol/water 1:1 and was acidified with hydrochloric acid (1 M) to pH 5. Under cooling (ice
bath), the respective aldehyde and KCN were added and the mixture was stirred until TLC
indicated complete conversion. Gaseous HCN was removed with a stream of argon
(CAUTION!) and the reaction mixture was extracted three times with diethyl ether. The
combined organic layers were washed with brine, dried over Na2SO4 and the solvent was
removed in vacuo.
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(2S,4’S,5’S)-(+)-2-Amino-N-(2’,2’-dimethyl-4’-phenyl-1’,3’-dioxan-5’-yl)-
7
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phenylacetonitrile (3a)
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The title compound was prepared according to the general procedure from amine 1 (2.98 g,
14.4 mmol) in H2O/MeOH (30 mL each), benzaldehyde (1.74 mL, 17.3 mmol) and KCN
(1.28 g, 18.7 mmol) during 20 h at room temperature. Yield: 3.78 g (11.7 mmol, 82%)
colorless crystals. Mp 111.4–112.0 °C (from EtOH), Lit.44: 14 °C. Rf: 0.52 (cyclohexane/ethyl
acetate 3:1). IR (ATR, cmꢀ1): ꢀ
̅ = 3330, 2992, 2873, 1451, 1381, 1198, 1072, 845, 743, 698.
1HꢀNMR, COSY, NOESY (400 MHz, CDCl3) ꢁ (ppm) = 7.45–7.08 (m, 10H, Har.), 5.17 (s, 1H,
Hꢀ4’), 4.30 (d, J = 11.9 Hz, 1H, Hꢀ6’a), 4.06 (d, J = 11.9 Hz, 1H, Hꢀ6’b), 3.89 (s, 1H, Hꢀ2), 2.94
(s, 1H, Hꢀ5’), 2.14 (s, 1H, NH), 1.56 (s, 3H, CH3ꢀa), 1.51 (s, 3H, CH3ꢀb). 13CꢀNMR, HSQC,
HMBC, NOESY (100.6 MHz, CDCl3) ꢁ (ppm) = 139.6 (C1’’’), 134.9 (C1’’), 129.0 (C4’’), 128.8
(C3’’,5’’), 128.4 (C4’’’), 127.7 (C3’’’,5’’’), 127.6 (C2’’,6’’), 126.1 (C2’’’,6’’’), 119.8 (C1), 99.4
(C2’), 73.3 (C4’), 64.9 (C6’), 54.8 (C5’), 54.0 (C2), 29.6 (CH3ꢀb), 18.7 (CH3ꢀa). ESIꢀHRMS:
m/z calcd. for [C20H22N2O2 + H]+: 323.1760, found 323.1764.
The analytical data are in accordance to those reported in the literature.44
(2S,4’S,5’S)-(+)-2-Amino-N-(2’,2’-dimethyl-4’-phenyl-1’,3’-dioxan-5’-yl)-(2-naphthyl)-
acetonitrile (3b)
The title compound was prepared according to the general procedure from amine 1 (770 mg,
3.71 mmol) in H2O/MeOH (10 mL each), 2ꢀnaphthaldehyde (696 mg, 4.46 mmol), and KCN
(314 mg, 4.83 mmol) during 22 h at room temperature. Yield: 925 mg (2.48 mmol, 67%),
colorless crystalline solid. Mp 122.5–123.2 °C (from EtOH). Rf: 0.45 (cyclohexane/ethyl
acetate 3:1). IR (ATR, cmꢀ1): ꢀ
̅ = 3340, 2992, 2872, 2246, 1693, 1451, 1380, 1198, 1073,
1
738, 700. HꢀNMR, COSY (400 MHz, CDCl3) ꢁ (ppm) = 7.85–7.71 (m, 3H, Har.), 7.58 (d,
J = 1.7 Hz, 1H, Har.), 7.54–7.47 (m, 2H, Har.), 7.47–7.37 (m, 5H, Har.), 7.12 (dd, J = 8.5,
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1.9 Hz, 1H, Har.), 5.18 (d, J = 2.2 Hz, 1H, Hꢀ4‘), 4.29 (dd, J = 12.0, 2.1 Hz, 1H, Hꢀ6‘a), 4.14–
4.07 (m, 2H, Hꢀ6‘b, Hꢀ2), 2.96 (m, 1H, Hꢀ5‘), 2.22 (t, J = 7.7 Hz, 1H, NH), 1.56 (s, 3H, Hꢀ13‘),
1.50 (s, 3H, Hꢀ14‘). 13CꢀNMR, HSQC, HMBC (100.6 MHz, CDCl3) ꢁ (ppm) = 139.7 (C1’’’),
133.5 (Cq,Naph.), 133.0 (Cq,Naph.), 132.3 (C2’‘), 128.8 (Car.), 128.5 (C3’’’,5’’’), 128.2 (Car.), 127.8
(Car.), 127.8 (Car.), 126.9 (Car.), 126.8 (Car.), 126.7 (Car.), 126.2 (C2’’’,6’’’), 125.2 (Car.), 119.8
(C1), 99.5 (C2’), 73.5 (C4’), 64.8 (C6’), 55.0 (C5’), 54.1 (C2), 29.7 (CH3ꢀb), 18.8 (CH3ꢀa). ESIꢀ
HRMS: m/z calcd for [C24H24N2O2 + Na]+: 395.1735, found 395.1731.
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General procedure for the alkylation of aminonitriles 4.
The alkylated aminonitriles 4 were prepared according to a modification of a protocol by
Enders et al.45 In a flameꢀdried round bottom flask, the starting aminonitrile 3 was dissolved
in dry THF (0.75 mL / 100 mg) under argon atmosphere. After cooling to –78 °C, a solution of
KHMDS (1.3 equiv.) in dry THF (1.25 mL/100 mg) was added. Shortly thereafter, the alkyl
halide (1.3 equiv.) was added as a solution in dry THF (1.00 mL / 100 ꢀL) and the mixture
was stirred at –78 °C until TLC indicated complete conversion. The dry ice bath was
removed and after 1 h, a saturated NaHCO3ꢀsolution was added and the mixture was
extracted three times with ethyl acetate. The combined organic layers were washed with
brine, dried over Na2SO4 and the solvent was removed in vacuo. Due to their instability
during chromatography, the alkylated aminonitriles 4 were subjected to the removal of the
auxiliary without further purification.
(2R,4’S,5’S)-2-Amino-N-(2’,2’-dimethyl-4’-phenyl-1’,3’-dioxan-5’-yl)-2-methyl-
phenylacetonitrile (4a)
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The title compound was prepared according to the general procedure from aminonitrile 3a
(300 mg, 0.93 mmol), KHMDS (241 mg, 1.21 mmol), and iodomethane (75.6 µL, 1.21 mmol)
during 2 h at −78 °C. the crude product (365 mg, yellowish oil) was directly subjected to the
removal of the auxiliary. Rt: (S,S,R) = 1.24 min (eluent: H2O/MeCN 50:50). Rf: 0.64
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(cyclohexane/ethyl acetate 5:1). IR (ATR, cmꢀ1): ꢀ
̅ = 3352, 2992, 2875, 1449, 1381, 1198,
845, 762, 698. 1HꢀNMR, COSY (300 MHz, CDCl3) ꢁ (ppm) = 7.34–7.27 (m, 3H, Hꢀ3’’’,5’’’,4’’),
7.19–7.08 (m, 3H, Hꢀ2’’’,6’’’,4’’’), 6.98 (t, J = 7.8 Hz, 2H, Hꢀ3’’,5’’), 6.79 (dd, J = 8.4, 1.1 Hz,
2H, Hꢀ2’’,6’’), 4.90 (d, J = 1.8 Hz, 1H, Hꢀ4’), 4.61 (dd, J = 12.3, 1.7 Hz, 1H, Hꢀ6’a), 4.06 (dd,
J = 12.2, 1.4 Hz, 1H, Hꢀ6’b), 2.55 (s, 1H, NH), 2.46 (s, 1H, Hꢀ5’), 1.64 (s, J = 5.6 Hz, 3H, ꢀ
CH3), 1.58 (s, 3H, CH3ꢀa), 1.52 (s, 3H, CH3ꢀb). 13CꢀNMR, HSQC, HMBC (75.5 MHz, CDCl3) ꢁ
(ppm) = 139.7 (C1’’’), 139.0 (C1’’), 128.5 (C3’’,5’’), 128.0 (C4’’), 127.9 (C3’’’,5’’’), 127.2
(C4’’’), 126.9 (C2’’’,6’’’), 125.8 (C2’’,6’’), 123.0 (C1), 99.3 (C2’), 75.1 (C4’), 62.5 (C6’), 58.1
(C2), 52.2 (C5’), 32.7 (CH3), 29.9 (CH3ꢀb), 18.6 (CH3ꢀa). ESIꢀMS: m/z = 279.1 (100%, [M –
CH3COCH3 + H]+), 337.1 (16.3%, [M + H]+). ESIꢀHRMS: m/z = calcd. for [C21H24N2O2 + Na]+:
359.1735, found 359.1729. No diastereomer detected by HPLC/MS and 2DꢀNMR.
(2R,4’S,5’S)-2-Amino-N-(2’,2’-dimethyl-4’-phenyl-1’,3’-dioxan-5’-yl)-2-ethyl-
phenylacetonitrile (4b)
The title compound was prepared according to the general procedure from aminonitrile 3a
(200 mg, 0.62 mmol), KHMDS (161 mg, 0.81 mmol) and bromoethane (60.2 µL, 0.81 mmol)
during 2 h at −78 °C. The crude product (226 mg, yellowish oil) was directly subjected to the
removal of the auxiliary. Rt: (S,S,R) = 2.02 min, (S,S,S) = 1.64 min (eluent: H2O/MeCN
50:50). Rf: 0.65 (cyclohexane/ethyl acetate 5:1). IR (ATR, cmꢀ1): ꢀ
̅ = 3351, 3029, 2878, 1452,
1
1382, 1200, 847, 760, 700. HꢀNMR, COSY (300 MHz, CDCl3) ꢁ (ppm) = 7.33–7.27 (m, 3H,
Hꢀ3’’’,5’’’’,4’’), 7.18–7.09 (m, 3H, Hꢀ2’’’,6’’’,4’’’), 6.97 (t, J = 7.8 Hz, 2H, Hꢀ3’’,5’’), 6.72 (dd,
J = 8.4, 1.1 Hz, 2H, Hꢀ2’’,6’’), 4.89 (d, J = 1.9 Hz, 1H, Hꢀ4’), 4.63 (dd, J = 12.3, 1.8 Hz, 1H, Hꢀ
6’a), 4.04 (dd, J = 12.2, 1.5 Hz, 1H, Hꢀ6’b), 2.63 (d, J = 10.5 Hz, 1H, NH), 2.46 (dd, J = 10.2,
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1.4 Hz, 1H, Hꢀ5’), 1.93 (dq, J = 14.6, 7.3 Hz, 1H, ꢀCH2CH3), 1.76 (dq, J = 15.0, 7.5 Hz, 1H, ꢀ
CH2CH3), 1.57 (s, 3H, CH3ꢀa), 1.52 (s, 3H, CH3ꢀb), 0.80 (t, J = 7.4 Hz, 3H, ꢀCH2CH3). 13Cꢀ
NMR, HSQC, HMBC (75.5 MHz, CDCl3) ꢁ (ppm) = 139.8 (C1’’’), 137.5 (C1’’), 128.4 (C3’’,5’’),
127.9 (C4’’), 127.9 (C3’’’,5’’’), 127.2 (C4’’’), 127.0 (C2’’’,6’’’), 126.5 (C2’’,6’’), 122.3 (C1), 99.3
(C2’), 75.2 (C4’), 63.5 (C2), 62.5 (C6’), 52.0 (C5’), 37.8 (CH2CH3), 30.0 (CH3ꢀb), 18.6 (CH3ꢀ
a), 8.9 (CH2CH3). ESIꢀMS: m/z = 293.1 (100%, [M – CH3COCH3 + H]+), 351.2 (30.3%,
[M + H]+). ESIꢀHRMS: m/z calcd. for [C22H26N2O2 + H]+: 351.2073, found 351.2089. No
diastereomer detected by HPLC/MS and 2DꢀNMR.
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(2R,4’S,5’S)-2-Amino-N-(2’,2’-dimethyl-4’-phenyl-1’,3’-dioxan-5’-yl)-2-benzyl-
phenylacetonitrile (4c)
The title compound was prepared according to the general procedure from aminonitrile 3a
(300 mg, 0.93 mmol), KHMDS (241 mg, 1.21 mmol), and benzyl bromide (143.7 µL,
1.21 mmol) during 2 h at −78 °C. The crude product (yellowish oil, 426 mg) was directly
subjected to the removal of the auxiliary. Rt: (S,S,R) = 4.13 min, (S,S,S) = 2.78 min (eluent:
H2O/MeCN 50:50). Rf: 0.67 (cyclohexane/ethyl acetate 5:1). IR (ATR, cmꢀ1): ꢀ
̅ = 3349, 2992,
1
2875, 2251, 1452, 1381, 1198, 1073, 908, 729, 697. HꢀNMR, COSY (300 MHz, CDCl3) ꢁ
(ppm) = 7.40–7.36 (m, 3H, Hꢀ3’’’,5’’’,4’’’), 7.34–7.30 (m, 3H, Hꢀ4Bn,3Bn,5Bn), 7.25–7.22 (m, 2H,
Hꢀ2’’’,6’’’), 7.19–7.12 (m, 3H, Hꢀ4’’,2Bn,6Bn), 6.98 (t, J = 7.8 Hz, 2H, Hꢀ3’’,5’’), 6.73 (d,
J = 7.3 Hz, 2H, Hꢀ2’’,6’’), 4.88 (d, J = 1.7 Hz, 1H, Hꢀ4’), 4.46 (dd, J = 12.2, 1.8 Hz, 1H, Hꢀ6’a),
3.89 (dd, J = 12.2, 1.3 Hz, 1H, Hꢀ6’b), 2.99 (d, J = 13.2 Hz, 1H, CH2Ph), 2.94 (d, J = 13.2 Hz,
1H, CH2Ph), 2.73 (d, J = 9.8 Hz, 1H, NH), 2.46 (d, J = 8.2 Hz, 1H, Hꢀ5’), 1.46 (s, 3H, CH3ꢀa),
1.40 (s, 3H, CH3ꢀb). 13CꢀNMR, HSQC, HMBC (75.5 MHz, CDCl3) ꢁ (ppm) = 139.9 (C1’’’),
137.9 (C1’’), 133.9 (C1Bn), 130.7 (C2Bn,6Bn), 128.5 (C3’’,5’’), 128.4 (C3Bn,5Bn), 128.2 (C4’’),
127.9 (C3’’’,5’’’), 127.9 (C4Bn), 127.3 (C4’’’), 127.0 (C2’’’,6’’’), 126.6 (C2’’,6’’), 121.9 (C1), 99.1
(C2’), 75.3 (C4’), 62.7 (C2), 61.7 (C6’), 51.8 (C5’), 51.2 (CH2Ph), 29.7 (CH3ꢀb), 18.5 (CH3ꢀa).
ESIꢀMS: m/z = 355.2 (100%, [M – CH3COCH3 + H]+), 413.2 (71.3%, [M + H]+). ESIꢀHRMS:
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m/z calcd. for [C27H28N2O2 + Na]+: 435.2048, found 435.2054. d.r. (S,S,R) / (S,S,S) > 19:1
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(HPLCꢀMS).
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(2R,4’S,5’S)-2-Amino-N-(2’,2’-dimethyl-4’-phenyl-1’,3’-dioxan-5’-yl)-2-propyl-
phenylacetonitrile (4d)
The title compound was prepared according to the general procedure from aminonitrile 3a
(300 mg, 0.93 mmol), KHMDS (241 mg, 1.21 mmol), and 1ꢀbromopropane (110.0 µL,
1.21 mmol) during 3 h at −78 °C. The crude product (yellowish oil, 341 mg) was directly
subjected to the removal of the auxiliary. Rt: (S,S,R) = 3.29 min, (S,S,S) = 2.60 min (eluent:
H2O/MeCN 50:50). Rf: 0.68 (cyclohexane/ethyl acetate 5:1). IR (ATR, cmꢀ1): ꢀ
̅ = 3351, 3030,
1
2875, 1665, 1451, 1381, 1199, 1073, 846, 763, 699. HꢀNMR, COSY (300 MHz, CDCl3) ꢁ
(ppm) = 7.33–7.27 (m, 3H, Hꢀ3’’’,5’’’,4’’), 7.18–7.08 (m, 3H, Hꢀ2’’’,6’’’,4’’’), 6.96 (t, J = 7.8 Hz,
2H, Hꢀ3’’,5’’), 6.72 (dd, J = 8.3, 1.1 Hz, 2H, Hꢀ2’’,6’’), 4.88 (d, J = 1.9 Hz, 1H, Hꢀ4’), 4.62 (dd,
J = 12.2, 1.7 Hz, 1H, Hꢀ6’a), 4.03 (dd, J = 12.2, 1.4 Hz, 1H, Hꢀ6’b), 2.62 (s, 1H, NH), 2.45 (s,
1H, Hꢀ5’), 1.91–1.82 (m, 1H, CH2ꢀCH2ꢀCH3), 1.73–1.64 (m, 1H, CH2ꢀCH2ꢀCH3), 1.57 (s, 3H,
CH3ꢀa), 1.51 (s, 3H, CH3ꢀb), 1.47–1.35 (m, 1H, CH2ꢀCH2ꢀCH3), 1.04 – 0.91 (m, 1H, CH2ꢀCH2ꢀ
CH3), 0.82 (t, J = 7.3 Hz, 3H, CH2ꢀCH2ꢀCH3). 13CꢀNMR, HSQC, HMBC (75.5 MHz, CDCl3) ꢁ
(ppm) = 139.8 (C1’’’), 137.8 (C1’’), 128.4 (C3’’,5’’), 180.0 (C4’’), 128.0 (C3’’’,5’’’), 127.2
(C4’’’), 127.0 (C2’’’,6’’’), 126.4 (C2’’,6’’), 122.5 (C1), 99.3 (C2’), 75.2 (C4’), 62.8 (C2), 62.5
(C6’), 51.9 (C5’), 46.7 (CH2ꢀCH2ꢀCH3), 30.0 (CH3ꢀb), 18.6 (CH3ꢀa), 17.9 (CH2ꢀCH2ꢀCH3), 13.8
(CH2ꢀCH2ꢀCH3). ESIꢀMS: m/z = 307.1 (100%, [M – CH3COCH3 + H]+), 365.2 (31.5%,
[M + H]+). ESIꢀHRMS: m/z calcd. for [C23H28N2O2 + H]+: 365.2229, found 365.2240. d.r.
(S,S,R) / (S,S,S) > 29:1 (HPLCꢀMS)
(2R,4’S,5’S)-2-Amino-N-(2’,2’-dimethyl-4’-phenyl-1’,3’-dioxan-5’-yl)-2-(2-propyl)-
phenylacetonitrile (4e)
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The title compound was prepared according to the general procedure from aminonitrile 3a
(150 mg, 0.47 mmol), KHMDS (121 mg, 0.60 mmol), and 2ꢀbromopropane (56.8 µL,
0.60 mmol) during 4 h at −78 °C. The crude product (yellowish oil, 181 mg) was directly
subjected to the removal of the auxiliary. Rt: (S,S,R) = 3.21 min, (S,S,S) = 2.00 min (eluent:
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H2O/MeCN 50:50). Rf: 0.63 (cyclohexane/ethyl acetate 5:1). IR (ATR, cmꢀ1): ꢀ
̅ = 3378, 2990,
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2875, 1665, 1451, 1381, 1200, 1096, 846, 760, 700. HꢀNMR, COSY (300 MHz, CDCl3) ꢁ
(ppm) = 7.33–7.29 (m, 3H, Hꢀ3’’’,5’’’,4’’), 7.21–7.08 (m, 3H, Hꢀ2’’’,6’’’,4’’’), 6.96 (t, J = 7.8 Hz,
2H, Hꢀ3’’,5’’), 6.69 (d, J = 7.3 Hz, 2H, Hꢀ2’’,6’’), 4.90 (d, J = 2.0 Hz, 1H, Hꢀ4’), 4.63 (dd,
J = 12.3, 1.8 Hz, 1H, Hꢀ6’a), 3.99 (dd, J = 12.3, 1.5 Hz, 1H, Hꢀ6’b), 2.81 (d, J = 10.7 Hz, 1H,
NH), 2.43 (dq, J = 10.7, 1.8 Hz, 1H, Hꢀ5’), 1.93 (sept, J = 6.7 Hz, 1H, CH(CH3)2), 1.57 (s, 3H,
CH3ꢀa), 1.52 (s, 3H, CH3ꢀb), 1.15 (d, J = 6.6 Hz, 3H, CH(CH3)2), 0.63 (d, J = 6.9 Hz, 3H,
CH(CH3)2). 13CꢀNMR, HSQC, HMBC (75.5 MHz, CDCl3) ꢁ (ppm) = 139.9 (C1’’’), 137.0 (C1’’),
128.2 (C3’’,5’’), 127.9 (C4’’), 127.8 (C3’’’,5’’’), 127.3 (C4’’’), 127.1 (C2’’’,6’’’), 127.0 (C2’’,6’’),
121.6 (C1), 99.3 (C2’), 75.4 (C4’), 67.4 (C2), 62.3 (C6’), 52.0 (C5’), 40.2 (CH(CH3)), 30.1
(CH3ꢀb), 18.6 (CH3ꢀa), 18.0 (CH3), 17.8 (CH3). ESIꢀMS: m/z = 307.2 (100%, [M –
CH3COCH3 + H]+), 365.2 (45.2%, [M + H]+). ESIꢀHRMS: m/z calcd. for [C23H28N2O2 + Na]+:
387.2048, found 387.2051. d.r. (S,S,R) / (S,S,S) > 4.4:1 (HPLCꢀMS).
(2S,4’S,5’S)-2-Amino-N-(2’,2’-dimethyl-4’-phenyl-1’,3’-dioxan-5’-yl)-2-
(methoxymethylen)-phenylacetonitrile (4f)
The title compound was prepared according to the general procedure from aminonitrile 3a
(100 mg, 0.31 mmol), KHMDS (80 mg, 0.40 mmol), and MOMCl (30.6 µL, 0.40 mmol) during
3 h at −78 °C. The crude product (yellowish oil, 120 mg) was directly subjected to the
removal of the auxiliary. Rt: (S,S,S) = 1.31 min, (S,S,R) = 1.02 min (eluent: H2O/MeCN
50:50). Rf: 0.50 (cyclohexane/ethyl acetate 5:1). IR (ATR, cmꢀ1): ꢀ
̅ = 3349, 2993, 2929, 1664,
1452, 1381, 1197, 1071, 973, 845, 749, 699. 1HꢀNMR, COSY (300 MHz, CDCl3) ꢁ
(ppm) = 7.34–7.28 (m, 3H, Hꢀ3’’’,5’’’,4’’), 7.23–7.11 (m, 3H, Hꢀ2’’’,6’’’,4’’’), 6.97 (t, J = 7.8 Hz,
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2H, Hꢀ3’’,5’’), 6.76 (dd, J = 8.4, 1.2 Hz, 2H, Hꢀ2’’,6’’), 4.92 (d, J = 2.0 Hz, 1H, Hꢀ4’), 4.62 (dd,
J = 12.3, 1.8 Hz, 1H, Hꢀ6’a), 4.05 (dd, J = 12.3, 1.6 Hz, 1H, Hꢀ6’b), 3.46 (s, 3H, ꢀOCH3), 3.34
(d, J = 9.3 Hz, 1H, ꢀCH2ꢀOCH3), 3.29 (d, J = 9.3 Hz, 1H, ꢀCH2ꢀOCH3), 2.48 (d, J = 5.7 Hz, 1H,
Hꢀ5’), 1.58 (s, 3H, CH3ꢀa), 1.53 (s, 3H, CH3ꢀb). 13CꢀNMR, HSQC, HMBC (75.5 MHz, CDCl3) ꢁ
(ppm) = 139.9 (C1’’’), 135.1 (C1’’), 128.6 (C4’’,3’’,5’’), 127.9 (C3’’’,5’’’), 127.2 (C4’’’), 127.1
(C2’’’,6’’’), 126.8 (C2’’,6’’), 121.5 (C1), 99.3 (C2’), 80.3 (CH2OMe), 75.2 (C4’), 63.1 (C2), 62.3
(C6’), 59.8 (OCH3), 51.8 (C5’), 29.9 (CH3ꢀb), 18.6 (CH3ꢀa). ESIꢀMS: m/z = 309.1 (100%, [M –
CH3COCH3 + H]+), 367.2 (48.0%, [M + H]+). ESIꢀHRMS: m/z calcd. for [C22H26N2O3 + Na]+:
389.1841, found 389.1833. d.r. (S,S,S) / (S,S,R) > 39:1 (HPLCꢀMS).
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(2R,4’S,5’S)-2-Amino-N-(2’,2’-dimethyl-4’-phenyl-1’,3’-dioxan-5’-yl)-2-ethyl-(2-naphthyl)-
acetonitrile (4g)
The title compound was prepared according to the general procedure from aminonitrile 3b
(250 mg, 0.67 mmol), KHMDS (174 mg, 0.87 mmol), and bromoethane (65.1 µL, 0.87 mmol)
during 3 h at −78 °C. The crude product (yellowish oil, 285 mg) was directly subjected to the
removal of the auxiliary. Due to the presence of impurities, the NMRꢀspectroscopic data were
not analyzed further. Rt: (S,S,R) = 5.39 min, (S,S,S) = 5.24 min (eluent: H2O/MeCN 40:60).
Rf: 0.62 (cyclohexane/ethyl acetate 5:1). IR (ATR, cmꢀ1): ꢀ
̅ = 3351, 2991, 2876, 1662, 1500,
1452, 1381, 1198, 1096, 847, 746, 699. ESIꢀMS: m/z = 343.2 (100%, [M – CH3COCH3 + H]+),
401.2 (42.9%, [M + H]+). ESIꢀHRMS: m/z calcd. for [C26H28N2O2 + Na]+: 423.2048, found
423.2046. d.r. (S,S,R) / (S,S,S) > 6:1 (HPLCꢀMS).
General procedure for the removal of the auxiliary with Raney nickel
Lactones 5 were prepared according to a protocol by Weinges et al..42 Concentrated
hydrochloric acid was cooled to −10 °C and the aminonitrile 4 was added. The mixture was
stirred for 1 h at −10 °C, for 1 h at 0 °C, for 1 h at room temperature and for another 4 h at
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55 °C. After removal of the solvent in vacuo, the crude product was washed with cold water
and was subjected to the catalytic oxidation without further purification. The crude lactone 5
was dissolved in aq. NaOH (2 M, 1.5 mL per 100 mg lactone) under warming. A suspension
of Raney nickel (100 mg, 50 wtꢀ%, per 100 mg lactone) in water was added and the mixture
was stirred under reflux (120 °C oil bath temperature) while a gentle stream of air is passed
through. After complete conversion (TLC), the hot mixture was filtered over kieselguhr and
neutralized by addition of hydrochloric acid. The solvent was removed in vacuo and the
remaining solid was taken up in ethanol to remove insoluble sodium chloride by filtration.
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Concentration in vacuo furnished the crude
HPLC.
αꢀamino acid which was purified by preparative
Determination of optical purity
A sample (2.5 ꢀmol) of the amio acid 6 was dissolved in water (50 ꢀL) and a 1%ꢀsolution of
Marfey’s reagent (3.7 ꢀmol, 1.4 equiv.) in acetone as well as an aqueous sodium bicarbonate
solution (1 M, 50 ꢀl) was added. The mixture was warmed to 40 °C until TLC indicated
complete conversion. The mixture was quenched by addition of hydrochloric acid (1 M) and
the ratio of the produced diastereomers was determined by analytical HPLC.
(R)-(−)-α-Methyl-α-phenylglycine (6a)
The title compound was prepared according to the general procedure from crude
aminonitrile 4a (260 mg) and concentrated hydrochloric acid (30 mL). The crude lactone 5a
was obtained as a colorless solid (143 mg). ESIꢀHRMS: m/z calcd. for [C18H19NO3 + Na]+:
320.1263, found 320.1265. Catalytic oxidation of a portion the lactone (70 mg) was
performed during 25 h. A portion (40 mg) of the crude product (60 mg) was purified by
preparative HPLC to yield a colorless amorphous solid (12 mg, 0.07 mmol, 33% over 3 steps
from 3a). Rt = 3.03 min (eluent: H2O/MeCN 97:3). Rf: 0.54 (ethyl acetate/2ꢀ
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butanone/H2O/HCO2H 5:3:1:1). [α]D = −27.3 (c = 0.5, H2O), Lit.53 [α]D −41.2 (c = 0.5, H2O).
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Lit.54 [α]D = −68.5 (c = 1.0, H2O), Mp 215.5–215.8 °C (lyophilized, amorphous), Lit.53: 260–
265 °C, Lit.54 (enantiomer): 260–265 °C (dec.). IR (ATR, cmꢀ1): ꢀ
̅ = 2958, 2925, 2855, 1731,
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1589, 1391, 1270, 695, 644. HꢀNMR, COSY (300 MHz, D2O) ꢁ (ppm) = 7.53–7.43 (m, 5H,
Har.), 1.90 (s, 3H, CH3). 13CꢀNMR, HSQC, HMBC (75.5 MHz, D2O) ꢁ (ppm) = 176.3 (CO2H),
137.6 (C1), 129.1 (Car.), 129.1 (Car.), 125.8 (Car.), 62.9 (Cα), 21.2 (CH3). ESIꢀMS: m/z = 166.0
(100%, [M + H]+), 149.0 (62.4%, [M – NH3 + H]+).
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e.r. (R)/(S) calcd. from Marfeyꢀmethod: 96:4. ee calcd. from Marfeyꢀmethod: 92%.
The analytical data match those reported in the literature.54
(R)-(−)-α-Ethyl-α-phenylglycine (6b)
The title compound was prepared according to the general procedure from crude
aminonitrile 4b (270 mg) and concentrated hydrochloric acid (30 mL). The crude lactone 5b
was obtained as a colorless solid (199 mg). ESIꢀHRMS: m/z calcd. for [C19H21NO3 + Na]+:
334.1419, found.: 334.1414. Catalytic oxidation of a portion the lactone (70 mg) was
performed during 26 h. A portion (47 mg) of the crude product (66 mg) was purified by
preparative HPLC to yield a colorless amorphous solid (17 mg, 0.09 mmol, 74% over 3 steps
from 3a). Rt = 3.85 min (eluent: H2O/MeCN 97:3). Rf: 0.63 (ethyl acetate/2ꢀ
butanone/H2O/HCO2H 5:3:1:1). [α]D = −17.3 (c = 1, H2O), Lit.53 [α]D: −20.8 (c = 0.5, H2O).
26
Lit.54 [α]D20: −23.7 (c = 1.0, H2O). ,. Mp 204.7–205.3 °C (lyophilized, amorphous), Lit.53: 248–
252 °C, Lit.54: (enantiomer): 250–255 °C (dec.). IR (ATR, cmꢀ1): ꢀ
̅ = 3360, 2956, 2924, 2854,
1732, 1600, 1372, 1287, 740, 697. 1HꢀNMR, COSY (300 MHz, D2O) ꢁ (ppm) = 7.53–7.31 (m,
5H, Har.), 2.27 (m, 2H, CH2CH3), 0.98 (t, J = 7.3 Hz, 3H, CH2CH3). 13CꢀNMR, HSQC, HMBC
(75.5 MHz, D2O) ꢁ (ppm) = 177.1 (CO2H), 139.5 (C1), 128.9 (Car.), 128.5 (Car.), 126.0 (Car.),
66.8 (Cα), 28.5 (CH2CH3), 7.7 (CH2CH3). ESIꢀMS: m/z = 180.0 (100%, [M + H]+), 163.0
(67.3%, [M – NH3 + H]+).
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e.r. (R)/(S) calcd. from Marfeyꢀmethod: 98.5:1.5. ee calcd. from Marfeyꢀmethod: 97%.
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The analytical data match those reported in the literature.54
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(R)-(+)-α-Benzyl-α-phenylglycine (6c)
The title compound was prepared according to the general procedure from crude
aminonitrile 4c (355 mg) and concentrated hydrochloric acid (30 mL). The crude lactone 5c
was obtained as a colorless solid (227 mg). ESIꢀHRMS: m/z calcd. for [C24H23NO3 + Na]+:
396.1576, found 396.1572. Catalytic oxidation of a portion the lactone (81 mg) was
performed during 68 h. A portion (26 mg) of the crude product (53 mg) was purified by
preparative HPLC to yield a colorless amorphous solid (22 mg, 0.09 mmol, 68% over 3 steps
from 3a). Rt = 2.52 min (eluent: H2O/MeCN 80:20). Rf: 0.76 (ethyl acetate/2ꢀ
butanone/H2O/HCO2H 5:3:1:1). [α]D = +16.6 (c = 0.5, DMSO), Lit.55 (enantiomer): [α]D
=
26
20
−28.1 (c = 0.5, 1 N HCl). Mp 199.7–200.5 °C (lyophilized, amorphous), Lit.56 (enantiomer):
268–269 °C (dec.). IR (ATR, cmꢀ1): ꢀ
̅
= 2957, 2925, 2855, 1731, 1595, 1383, 1273, 699, 644.
1HꢀNMR, COSY (400 MHz, CD3OD) ꢁ (ppm) = 7.68–7.61 (m, 2H, Har.), 7.4–7.31 (m, 3H, Har.),
7.30–7.19 (m, 5H, Har.), 3.72 (d, J = 14.1 Hz, 1H, CH2Ph), 3.42 (d, J = 14.1 Hz, 1H, CH2Ph).
13CꢀNMR, HSQC, HMBC (100.6 MHz, CD3OD) ꢁ (ppm) = 174.3 (CO2H), 140.6 (C1‘), 136.1
(C1), 131.7 (Car.), 129.7 (Car.), 129.7 (Car.), 129.4 (Car.), 128.6 (Car.), 127.3 (Car.), 68.5 (Cα),
43.4 (CH2Ph). ESIꢀMS: m/z = 242.0 (100%, [M + H]+), 225.0 (67.3%, [M – NH3 + H]+).
e.r. (R)/(S) calcd. from alkylated αꢀaminonitrile: >19:1, calcd. from Marfeyꢀmethod: 95.5:4.5.
ee calcd. from alkylated αꢀaminonitrile: >90%, calcd. from Marfeyꢀmethod: 91%.
The analytical data match those reported in the literature.56
(R)-(−)-α-Propyl-α-phenylglycine (6d)
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The title compound was prepared according to the general procedure from crude
aminonitrile 4d (262 mg) and concentrated hydrochloric acid (30 mL). The crude lactone 5d
was obtained as a colorless solid (203 mg). ESIꢀHRMS: m/z calcd. for [C20H23NO3 + Na]+:
348.1576, found 348.1587. Catalytic oxidation of a portion the lactone (60 mg) was
performed during 48 h. A portion (23 mg) of the crude product (37 mg) was purified by
preparative HPLC to yield a colorless amorphous solid (8 mg, 0.04 mmol, 33% over 3 steps
from 3a). Rt = 6.60 min (eluent: H2O/MeCN 97:3). Rf: 0.68 (ethyl acetate/2ꢀ
butanone/H2O/HCO2H 5:3:1:1). [α]D26 = −3.0 (c = 0.4, D2O), Lit.57 [α]D: −20 (c = 0.5, H2O). Mp
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225.5–226.0 °C (lyophilized, amorphous), Lit.53 (enantiomer): >300 °C (dec.). IR (ATR, cmꢀ1):
1
ꢀ̅
= 3375, 2960, 2927, 2871, 1731, 1596, 1363, 1288, 694. HꢀNMR, COSY (600 MHz,
CD3OD) ꢁ (ppm) = 7.56–7.49 (m, 2H, Hꢀ2,6), 7.39–7.33 (m, 2H, Hꢀ3,5), 7.33–7.26 (m, 1H, Hꢀ
4), 2.27–2.13 (m, 2H, CH2CH2CH3), 1.47–1.32 (m, 2H, CH2CH2CH3), 0.98 (t, J = 7.3 Hz, 3H,
CH2CH2CH3). 13CꢀNMR, HSQC, HMBC (151 MHz, CD3OD) ꢁ (ppm) = 175.1 (CO2H), 140.8
(C1), 129.7 (C3,5), 129.2 (C4), 127.2 (C2,6), 68.0 (Cα), 39.7 (CH2CH2CH3), 18.4
(CH2CH2CH3), 14.6 (CH2CH2CH3). ESIꢀMS: m/z = 177.0 (100%, [M – NH3 + H]+), 194.0
(49.2%, [M + H]+).
e.r. (R)/(S) calcd. from alkylated αꢀaminonitrile: >29:1, calcd. from Marfeyꢀmethod: 98:2. ee
calcd. from alkylated αꢀaminonitrile: >93%, calcd. from Marfeyꢀmethod: 96%.
The analytical data match those reported in the literature.57
(R)-(−)-α-(2-Propyl)-α-phenylglycine (6e)
The title compound was prepared according to the general procedure from crude
aminonitrile 4e (150 mg) and concentrated hydrochloric acid (30 mL). The crude lactone 5e
was obtained as a colorless solid (141 mg). ESIꢀHRMS: m/z calcd. for [C20H23NO3 + Na]+:
348.1576, found 348.1574. Catalytic oxidation of a portion the lactone (66 mg) was
performed during 46 h. A portion (33 mg) of the crude product (50 mg) was purified by
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preparative HPLC to yield a colorless amorphous solid (5 mg, 0.03 mmol, 21% over 3 steps
4
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from 3a). Rt = 8.56 min (eluent: H2O/MeCN 97:3). Rf: 0.56 (ethyl acetate/2ꢀ
6
7
8
26
20
butanone/H2O/HCO2H 5:3:1:1). [α]D = −20.6 (c = 0.4, D2O), Lit.58 ((S)ꢀenantiomer): [α]D
=
+20.0 (c = 0.7, 1 N HCl). Mp 219.8–220.4 °C (lyophilized, amorphous) Lit.58: (enantiomer):
242 °C. IR (ATR, cmꢀ1): ꢀ
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̅
= 3391, 2958, 2926, 2856, 1731, 1600, 1377, 1286, 1123, 740,
1
698. HꢀNMR, COSY (600 MHz, CD3OD) ꢁ (ppm) = 7.56 (d, J = 7.9 Hz, 2H, Hꢀ2,6), 7.34 (t,
J = 7.6 Hz, 2H, Hꢀ3,5), 7.27 (t, J = 7.3 Hz, 1H, Hꢀ4), 2.87 (h, J = 7.1 Hz, 1H, CH(CH3)2), 1.08
(d, J = 6.9 Hz, 3H, CH3), 0.80 (d, J = 7.0 Hz, 3H, CH3). 13CꢀNMR, HSQC, HMBC (151 MHz,
CD3OD) ꢁ (ppm) = 174.7 (CO2H), 140.3 (C1), 129.4 (C3,5), 128.7 (C4), 126.9 (C2,6), 71.9
(Cα), 35.0 (CH(CH3)2), 18.2 (CH3), 16.8 (CH3). ESIꢀMS: m/z = 194.0 (100%, [M + H]+), 176.9
(28.3%, [M – NH3 + H]+).
e.r. (R)/(S) calcd. from alkylated αꢀaminonitrile: >4.4:1, calcd. from Marfeyꢀmethod: 90:10. ee
calcd. from alkylated αꢀaminonitrile: >63%, calcd. from Marfeyꢀmethod: 80%.
The analytical data match those reported in the literature.58
(S)-(−)-α-(Methoxymethyl)-α-phenylglycine (6f)
The title compound was prepared according to the general procedure from crude
aminonitrile 4f (96 mg) and concentrated hydrochloric acid (30 mL). The crude lactone 5f
was obtained as a colorless solid (100 mg). ESIꢀHRMS: m/z calcd. for [C19H21NO4 + Na]+:
350.1368, found 350.1373. Catalytic oxidation of a portion the lactone (55 mg) was
performed during 24 h. A portion (38 mg) of the crude product (51 mg) was purified by
preparative HPLC to yield a colorless amorphous solid (16 mg, 0.08 mmol, 81% over 3 steps
from 3a). Rt = 2.52 min (eluent: H2O/MeCN 80:20). Rf: 0.53 (ethyl acetate/2ꢀ
butanone/H2O/HCO2H 5:3:1:1). [α]D = −5.4 (c = 1, D2O). IR (ATR, cmꢀ1): ꢀ
̅ = 3061, 2928,
26
1598, 1391, 1367, 1196, 1104, 737, 698. 1HꢀNMR, COSY (600 MHz, CD3OD) ꢁ (ppm) = 7.51
(d, J = 7.6 Hz, 2H, Hꢀ2,6), 7.34 (t, J = 7.4 Hz, 2H, H3,5), 7.29 (t, J = 7.3 Hz, 1H, Hꢀ4), 4.13–
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4.03 (m, 1H, CH2OMe), 3.98–3.89 (m, 1H, CH2OMe), 3.39 (s, 3H, OCH3). 13CꢀNMR, HSQC,
HMBC (151 MHz, CD3OD) ꢁ (ppm) = 173.8 (CO2H), 138.5 (C1), 129.7 (C3,5), 129.4 (C4),
127.2 (C2,6), 75.9 (CH2OMe), 67.5 (Cα), 59.5 (OCH3). ESIꢀHRMS: m/z calcd. for
[C10H13NO3 + Na]+: 218.0793, found 218.0789.
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e.r. (R)/(S) calcd. from alkylated αꢀaminonitrile: >39:1, calcd. from Marfeyꢀmethod: >99:1. ee
calcd. from alkylated αꢀaminonitrile: >95%, calcd. from Marfeyꢀmethod: >98%.
(R)-(−)-α-Ethyl-α-(2-naphthyl)-glycine (6g)
The title compound was prepared according to the general procedure from crude
aminonitrile 4g (225 mg) and concentrated hydrochloric acid (30 mL). The crude lactone 5g
was obtained as a colorless solid (235 mg). ESIꢀHRMS: m/z calcd. for [C23H23NO3 + Na]+:
384.1576, found 384.1577. Catalytic oxidation of a portion the lactone (70 mg) was
performed during 24 h. A portion (34 mg) of the crude product (49 mg) was purified by
preparative HPLC to yield a colorless amorphous solid (12 mg, 0.05 mmol, 49% over 3 steps
from 3b). Rt = 2.22 min (eluent: H2O/MeCN 80:20). Rf: 0.64 (ethyl acetate/2ꢀ
butanone/H2O/HCO2H 5:3:1:1). [α]D26 = −3.8 (c = 1, CD3OD). IR (ATR, cmꢀ1): ꢀ
̅ = 3359, 3059,
2935, 1600, 1559, 1393, 1379, 796, 749. 1HꢀNMR, COSY (600 MHz, CD3OD) ꢁ
(ppm) = 8.05–7.03 (m, 7H, Har.), 2.56–2.18 (m, 2H, CH2CH3), 1.02 (s, 3H, CH2CH3). 13Cꢀ
NMR, HSQC, HMBC (151 MHz, CD3OD) ꢁ (ppm) = 174.0 (CO2H), 134.5 (Car.), 132.9 (Car.),
128.9 (Car.), 128.6 (Car.), 128.0 (Car.), 127.1 (Car.), 126.8 (Car.), 126.4 (Car.), 126.1 (Car.), 125.6
(Car.), 74.8 (Cα), 29.1 (CH2CH3), 7.4 (CH2CH3). ESIꢀHRMS: m/z calcd. for [C14H15NO2 + H]+:
230.1181, found 230.1190.
e.r. (R)/(S) calcd. from alkylated αꢀaminonitrile: >6:1, calcd. from Marfeyꢀmethod: 97:3
ee calcd. from alkylated αꢀaminonitrile: >71%, calcd. from Marfeyꢀmethod: 94%.
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Acknowledgment
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We thank Professor G. Helmchen (Heidelberg) for a kind donation of auxiliary 1.
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Supporting Information
Supporting Information: NMR spectra of crude alkylation products 4 and of amino acids 6 as
well as HPLC chromatograms of Marfeyꢀderivatives. This material is available free of charge
via the Internet at http://pubs.acs.org/."
References
(1)
(2)
(3)
(4)
Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875.
Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584.
Perdih, A.; Dolenc, M. S. Curr. Org. Chem. 2007, 11, 801.
Ager, D. J. In Amino Acids, Peptides and Proteins in Organic Chemistry;
WileyꢀVCH Verlag GmbH & Co. KGaA: 2009, p 495.
(5)
(6)
Maruoka, K. Chem. Rec. 2010, 10, 254.
Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Peptide Science 2001, 60,
396.
(7)
(8)
Toniolo, C.; Formaggio, F.; Kaptein, B.; Broxterman, Q. B. Synlett 2006, 2006,
Seebach, D.; Sting, A. R.; Hoffmann, M. Angewandte Chemie International
1295.
Edition in English 1996, 35, 2708.
(9) Cativiela, C.; DıazꢀdeꢀVillegas, M. a. D. Tetrahedron: Asymmetry 1998, 9,
́
3517.
(10) Cativiela, C.; DıazꢀdeꢀVillegas *, M. a. D. Tetrahedron: Asymmetry 2000, 11,
́
645.
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1
2
3
4
5
6
7
(11) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127.
(12) Cativiela, C.; DíazꢀdeꢀVillegas, M. D. Tetrahedron: Asymmetry 2007, 18, 569.
(13) Undheim, K. Amino Acids 2008, 34, 357.
8
9
(14) Cativiela, C.; Ordóñez, M. Tetrahedron: Asymmetry 2009, 20, 1.
(15) Jautze, S.; Peters, R. Synthesis 2010, 365.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(16) Tomohara, K.; Yoshimura, T.; Hyakutake, R.; Yang, P.; Kawabata, T. J. Am.
Chem. Soc. 2013, 135, 13294.
(17) Bera, K.; Namboothiri, I. N. N. Asian J. Org. Chem. 2014, 3, 1234.
(18) Metz, A. E.; Kozlowski, M. C. J. Org. Chem. 2015, 80, 1.
(19) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.
(20) Albright, J. D. Tetrahedron 1983, 39, 3207.
(21) Stork, G.; Tang, P. C.; Casey, M.; Goodman, B.; Toyota, M. J. Am. Chem.
Soc. 2005, 127, 16255.
(22) BeaufortꢀDroal, V.; Pereira, E.; Thery, V.; Aitken, D. J. Tetrahedron 2006, 62,
11948.
(23) Enders, D.; Milovanovic, M. Z. Naturforsch., B: Chem. Sci. 2007, 62, 117.
(24) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359.
(25) Otto, N.; Opatz, T. Chem. ꢀ Eur. J. 2014, 20, 13064.
(26) Opatz, T.; Ferenc, D. Org. Lett. 2006, 8, 4473.
(27) Bergner, I.; Opatz, T. J. Org. Chem. 2007, 72, 7083.
(28) Kison, C.; Opatz, T. Chem. ꢀ Eur. J. 2009, 15, 843.
(29) Kison, C.; Meyer, N.; Opatz, T. Angew. Chem., Int. Ed. 2005, 44, 5662.
(30) Bergner, I.; Opatz, T. Synthesis 2007, 918.
(31) Leete, E.; Chedekel, M. R.; Bodem, G. B. J. Org. Chem. 1972, 37, 4465.
(32) Grierson, D. S.; Royer, J.; Guerrier, L.; Husson, H. P. J. Org. Chem. 1986, 51,
4475.
(33) Gauthier, I.; Royer, J.; Husson, H.ꢀP. J. Org. Chem. 1997, 62, 6704.
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2
3
(34) GillaizeauꢀGauthier, I.; Royer, J.; Husson, H.ꢀP. Eur. J. Org. Chem. 2002,
4
5
1484.
6
7
8
9
(35) Amorde, S. M.; Judd, A. S.; Martin, S. F. Org. Lett. 2005, 7, 2031.
(36) Werner, F.; Blank, N.; Opatz, T. Eur. J. Org. Chem. 2007, 3911.
(37) Blank, N.; Opatz, T. J. Org. Chem. 2011, 76, 9777.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(38) Imbri, D.; Tauber, J.; Opatz, T. Chem. ꢀ Eur. J. 2013, 19, 15080.
(39) Geffe, M.; Opatz, T. Org. Lett. 2014, 16, 5282.
(40) Meyer, N.; Opatz, T. Synlett 2003, 1427.
(41) García Ruano, J. L.; MartínꢀCastro, A. M.; Tato, F.; Alonso, I. J. Org. Chem.
2007, 72, 5994.
(42) Weinges, K.; Graab, G.; Nagel, D.; Stemmle, B. Chem. Ber. 1971, 104, 3594.
(43) Weinges, K.; Stemmle, B. Chem. Ber. 1973, 106, 2291.
(44) Weinges, K.; Brune, G.; Droste, H. Liebigs Ann. Chem. 1980, 1980, 212.
(45) Enders, D.; Gerdes, P.; Kipphardt, H. Angew. Chem., Int. Ed. Engl. 1990, 29,
179.
(46) Enders, D.; Mannes, D.; Raabe, G. Synlett 1992, 837.
(47) Enders, D.; Kirchhoff, J.; Mannes, D.; Raabe, G. Synthesis 1995, 659.
(48) Marfey, P. Carlsberg Res. Commun. 1984, 49, 591.
(49) Fujii, K.; Ikai, Y.; Mayumi, T.; Oka, H.; Suzuki, M.; Harada, K.ꢀi. Anal. Chem.
1997, 69, 3346.
(50) Saari, W. S.; Williams, J.; Britcher, S. F.; Wolf, D. E.; Kuehl, F. A. J. Med.
Chem. 1967, 10, 1008.
(51) Trišović, N.; Timić, T.; Divljaković, J.; Rogan, J.; Poleti, D.; Savić, M.;
Ušćumlić, G. Monatsh. Chem. 2012, 143, 1451.
(52) Enders, D.; Kirchhoff, J.; Gerdes, P.; Mannes, D.; Raabe, G.; Runsink, J.;
Boche, G.; Marsch, M.; Ahlbrecht, H.; Sommer, H. Eur. J. Org. Chem. 1998, 1998, 63.
(53) Cativiela, C.; Diaz de Villegas, M. D.; Galvez, J. A.; Lapena, Y. An. Quim.
1994, 90, 432.
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(54) Knabe, J.; Urbahn, C. Liebigs Ann. Chem. 1971, 750, 21.
4
5
6
7
(55) Hartwig, W.; Schöllkopf, U. Liebigs Ann. Chem. 1982, 1982, 1952.
(56) Goodson, L. H.; Honigberg, I. L.; Lehman, J. J.; Burton, W. H. J. Org. Chem.
8
9
1960, 25, 1920.
(57) Cativiela, C.; Villegas, M. D. D. d.; Galvez, J. A.; Lapena, Y. An. Quim. 1994,
90, 432.
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(58) Chaari, M.; Jenhi, A.; Lavergne, J.ꢀP.; Viallefont, P. Tetrahedron 1991, 47,
4619.
ACS Paragon Plus Environment